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Seeing a world of possibility in a single cell

For years, scientists have searched for ways to fix damaged hearts. Now, they may be getting closer to a breakthrough.

The human heart is notoriously tough to repair, a problem that has long stymied scientists and complicated care for patients.

Unlike the skin or bones, which readily heal by stitching together wounds or breaks with new, healthy cells, heart muscle cells largely lose their ability to replicate early in life (instead, they begin preparing for cell division but, in most cases, do not actually divide). Often, this means that the only way to fix damage to one of our most vital organs is through surgery or, in the most extreme cases, a heart transplant.

But that may be changing thanks to information gleaned by studying the slight differences between the cells that comprise the heart. These insights are helping scientists like Dr. Stefan Jovinge zero in on personalized treatments for repairing malformations that occur before birth, such as congenital heart defects (CHD), or damage from injury such as heart attacks.

“Detailed categorization of individual cells gives us an entirely new perspective on the causes of disease and possible new treatments,” Jovinge said. “Every single cell has a story to tell.”

Flipping the right switches Each of the more than 37 trillion cells that comprise the human body contain an almost identical copy of DNA, a nearly six-foot-long molecule that contains all of the instructions for making a human. But it’s the fluctuations in how this information is transcribed, accessed and acted upon that chart cells’ destiny, pushing one cell to become a heart muscle cell and another cell to become a blood cell.

For this to happen, cells rely on a process known as gene expression, during which the instructions in discrete parts of the DNA called genes are read and used to make proteins. Known as the worker bees of the body, proteins are involved in every, single biological function, from regulating body temperature to aiding in digestion.

Occasionally, there is a problem that changes a gene, causes the wrong gene to be read or causes the correct gene to be skipped over. When this happens, cells can go haywire, resulting in one of a multitude of conditions, from cancer to disorders like CHD.

In the past few decades, large-scale sequencing projects, in which scientists exhaustively catalog genes and gene expression, have been transformed how we look for these disease-related aberrations. But now, thanks to technological advances, scientists like Jovinge are able to take a hyper-focused look at all genes expressed in single cells in startling clarity.

Matching treatments to rare diseasesThe desire to study single cells in great detail isn’t new. The first single-cell protocol was developed in the early 1990s but it’s only relatively recently that technology has advanced enough to propel the kind of innovation underway in Jovinge’s lab.

He and his team are comparing individual cells — healthy and sick — to identify differences in their gene expression patterns, which act like a fingerprint. For example, if certain genes are active in a healthy cell but are switched off in the sick cell, that’s a good indication that those genes may be contributing to the problem affecting the cell.

Once identified, they check this genetic “fingerprint” against a massive database containing gene activity information for 20,000 compounds, many of which are already approved for use in the clinic, in hopes of finding a treatment that corrects problems in the sick cell.

Jovinge’s method is a unique take on drug repurposing, an approach that can save precious time and resources because these medications have already run the rigorous gauntlet of safety and efficacy trials required for use in patients. It holds particular significance for rare diseases, which often don’t receive the same amount of research funding as more common disorders.

Currently, it takes 10 to 15 years and more than $2 billion to translate an idea in a laboratory into a medication approved for use in patients. For people with rare diseases, which by definition affect anywhere from a handful of people to up to 200,000, these wait times are often much longer; because the patient numbers of smaller, its much more difficult to secure resources to develop new therapies.

So far, Jovinge’s team had some promising hits, and are continuing their efforts to match existing medications with diseases that have complementary gene expression profiles, much like pairing keys with locks. It’s an exhaustive process but one that is still markedly shorter than the traditional development timeline for a new medication. That fact alone makes it more than worth it.

“Heart problems, regardless of the cause, can have a major impact on quality of life. Right now, we can treat symptoms but without surgical intervention, we don’t have a good fix for many of these issues,” Jovinge said. “Studying disease at the single cell level may hold the key. If we can find new therapies, particularly if there are existing medications that will do the trick, that could have a profound, positive impact on people around the world.”

Read more: Matching keys to locks

Each compound in Jovinge’s database works by linking up with a specific molecule (or molecules) in the body, much like a key fitting into a lock. By figuring out which keys open which locks, they can match compounds to molecules, such a proteins, associated with specific diseases, possibly finding new treatments.

But they’re not just looking at one gene at a time. By evaluating the broader impact across a wide swath of genes , they can develop a “fingerprint” of the total effect of each compound. They then can compare a heart muscle cell from a patient with a rare heart disease to a healthy heart muscle cell, and search the database for the drug with the best matching “fingerprint” that reverses the abberrent gene expression in the sick cell. From there, they can test the compound on the sick cells in a petri dish to see if it works. Because these compounds are already approved for use, this approach can significantly shorten the time it takes to get new treatments to patients.

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Established by Jay and Betty Van Andel in 1996, Van Andel Institute is committed to improving the health and changing the lives of current and future generations, through biomedical research and science education.